3-substituted-9-methyl-3, 9-diazabicyclo [3.3.1] nonanes



United States Patent 3,96,154 3- SUBSTITUTED-9-IWETHYL-3,9-DIAZABHCYCLO [3.3.1]N9NANES Edgar A. dtech, La Grange, Ill, assignor to Sterling Drug Inc, New York, N,Y., a corporation of Delaware N0 Drawing. Filed May 17, 1962, Ser. No. 195,429 21' Claims. (Cl. 269-263) This invention relates to new and useful chemical compounds which have the 3,9-diazabicyclo[3.3.1]nonane ring system,

and also to intermediates and processes used in the preparation of the novel heterocyclic compounds.

Specifically, in one of its aspects, my invention relates to 3-R-9-rnethyl-3,9-diazabicyclo[3.3.1]nonanes having, in the form of their free bases, the structural formula (I) GH OH-CE CH: N-GHs N-R CH GH2 CH1 where R is a member selected from the group consisting of lower alkyl; lower alkyl substituted by a substituent selected from the group consisting of hydroxy, lower alkyl-O, NH lower alky-l-NH, d-i(lower alkyl)N, lower alkylmercapto, di(lower alkyDcarbamyl, lower alkyl- OCC- and carbomdi(lower alkyl) aminoalkyl-oxy groups; lower alkenyl, lower alkynyl, carbo-lower alkyloxy; thiocarbamyl substituted by a member selected from the group consisting of ally-l, monoand bicyclic aryl, monocarbocyclic-aryl-methyl, and his(monocarbocyclicaryDmethyl radicals; lower alkanesulfonyl; monocarbocyclic arenesulfonyl; di(lower alkyl)sulfarnyl; mono carbocyclioaryl; monocarbocyclic-aryllower-alkyl having from one to three substituents on the aromatic ring, and his(monocarbocyclic-aryl)methyl.

In another of its aspects my invention relates to intermediates for the preparation of the compounds of Formula I, said intermediates having the formula (II) CH2CH 0:0

C NCHa NR cn,o1-120=o where R has the meaning given above.

In still another aspect, my invention relates to processes for preparing 3 substituted 9 methyl 3,9 diazabicyclo[3.3.l]nonanes which comprises reacting l-loweralkyl-2,6-bis(carbalkoxy)piperidine having the formula Alkyl-O o owith a primary amine RNH where R is defined above, forming the 3-R-9-methyl 2,4 dioxo-3,9-diazabicycl-o [3.3.1]nonan-es of Formula II, and subsequently reducing the latter compounds with a reducing agent efiective for reducing cyclic imides to cyclic amines. An alternative procedure for preparing compounds of Formula I wherein R is a substituent other than aryl comprises preparing the compounds of Formula I wherein R is benzyl, according to the above procedure, reduct-ively dehenzylating said compounds according to known hydrogenolysis procedures, and alkylating or acylating the resulting 3-unsubstituted-9-methyl-3,Q-diazabicyclo{3.3.1]n0nane with an alkylating or acylating agent, respectively.

In Formula I, when representing lower alkyl radicals,

3.,l%,l54 Patented .luly 20, 1965 R is a straightor branched-chain saturated hydrocarbon radical having from one to six carbon atoms. Examples of lower alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isohutyl, n-amy], n-hexyl radicals, and the like.

When R represents lower alkyl substituted by a substituent selected from the group consisting of hydroxy, lower alkyl-O, Nil-I lower alkyl-NH, di(lower alkyl)N, lower alkylmercapto, di(lower aIkyDcarbamyl, lower alkyl-O-CO and carbo-w-diflowei' alkyl)aminoalkyl-oxy groups, the substituted lower alkyl group contains from 2 to 6 carbon atoms.

The hydroxy-substituted lower alkyl groups contain a hydroxyl group attached at any available position on the alkyl chain. The preferred hydroxy-substituted alkyl groups contain a hydroxyl group or the terminal or w-carbon, the reactants for preparing compounds having such suhstituents being readily available. Examples of hydroxysubstituted lower alkyl groups include Z-hydroxyethyl, 3- hydroxypropyl, r-hydroxybutyl, S-hydroxypentyl, and 6- hydroxyhexyl.

Lower alkyl-O-substituted lower alkyl groups are commonly called lower alkoxyalkyl groups. The prederred lower alkoxyalkyl substituents bear the alkoXy group in the terminal position of the alkyl chain. EX- amples of such lower alkyl-G-substituted alkyl groups include Z-methoxyethyl, Z-ethoxyethyl, S-methoxypropyl, o-methoxyhexyl, 4-butoxybutyl, Z-hexyloxyethyl, and the like.

Lower alkyl groups substituted by NH lower alkyl- NH, and di(lower alkyl)N are primary-, secondary-, and tertiary-amino-lower alkyl groups. The preferred primary-, secondary-, and tertiary-amino-lower alkyl groups contain the amine substituent on the terminal carbon atom of the lower alkyl chain. Examples of lower alkyl groups substituted by NH lower alkyl-NH, and di(lower alkyl)N include Z-aminoethyl, 3-aminopropyl, 6-aminohexyl, 4-propylaminobutyl, S-methylaminopentyl, 2-dimethylaminoethyl, Z-diethylaminoethyl, 3-dimethylaminopropyl, diethylaminohexyl, and the like. In addition, the tertiary-amino group may be a member of a saturated heterocyclic ring such as piperidino, yrrolidino, piperazino, carbazolino, and the like. Examples of such tertiary-aminoalkyl groups are 2-piperidiuoethyl, 3-pyrrolidinopropyl, 2-(5-carbazolyl)ethyl, 4-methylpiperazin0- ethyl, 3-'(4-carbethoxypiperazino)propyl, and the like.

The lower alkylmercapto-substituted lower alkyl groups have a lower alkylmercapto substituent attached at any one available position on the alkyl chain. Preferred lower alkylmercapto lower alkyl groups contain a lower alkylrnercapto substituent on the terminal or w-carbon atom. Examples of such lower alkylrnercapto-substituted lower alkyl groups are Z-methyl-mercaptoethyl, S-ethylmercaptopropyl, 6-methylmercaptohcxyl, and the like.

Examples of di(l0wer alkyl)carbamyl-substituted lower alkyl groups are diethylcarbamylmethyl, dimethylcarbamylethyl, dimethylcarbamylhexyl, and the like.

When representing lower alkyl groups substituted by carbo-w-di(iower alkyllaminoalkyl-oxy groups, R is di- (lower alkyl)N(CH -()CO-lower alkyl-, where n is an integer from 2 to 6. Examples of carbo-w-diflower alkyl)aminoalkyl-oxy-substituted lower alkyl groups include (carbO-Z-diethylaminOethoXy)methyl, (carbo-3- dimethylaminopropoxy)ethyl, (carbo-4diethylaminobutoxy)hexyl, and the like.

When representing alkenyl, R is a straightor branchedchain hydrocarbon radical containing one or two double bonds and containing from three to six carbon atoms. Examples of alkenyl radicals include allyl, methallyl, I-(S-heXenyl), l-(2,4-pentadienyl), and the like.

When representing alkynyl, R is a straightor branchedchain hydrocarbon radical containing a triple-bond. Ex-

arsensa amples of alkyny-l radicals include propargyl, I-(Z-butynyl), and l-(3-hexynyl) radicals.

When R represents a carbo-lower-alkoxy radical, it is lower alkyl-O-CO-, wherein lower alkyl is as defined above. Examples of such carbo-lower-alkoxy radicals are carbomethoxy, carbethoxy, carbopropoxy, carbohexyloxy, and the like.

When R represents thiocarbamyl radicals substituted by a member selected from the group consisting of allyl, 'monoand bicyclic-aryl, monocarbocyclic-aryl-methyl, and bis(monocarbocyclic-aryl)methyl, the monoand bicyclic-aryl groups can be of the carbocyclic or of the 'heterocyclic class. They have one or two rings and can be substituted by from one to three substituents of low molecular weight. The monocarbocyclic-aryl-methyl groups are unsubstituted benzyl or benzyl substituted with from one to three substituents of low molecular weight. The bis(monocarbocyclic-aryl) methyl groups are unsubstituted benzhydryl or benzhydryl substituted 'in either or both rings with from one to three substituents of low molecular weight. The substituents attached to either aryl or aralkyl radicals can be the same or different, and have a'total molecular weight less than 200. Examples of suitable substituents are hydroxy, lower alkoxy, lower alkylmercapto, halo, nitro, lower alkyl, amino, trifiuoromethyl, and the like. Preferred monoand bicyclic-aryl radicals are phenyl or naphthyl, each either unsubstituted or substituted with from one to three substituents of low molecular weight. Examples of such substituted thiocarbamyl radicals include phenylthiocarbamyl, 4-pyridyl-thiocarbamyl, '4-chlorophenyl-thiocarbamyl 6-(4-amino-Z-methylquinolinylJ:-thiocarbamyl, 2- furyl-thiocarbamyl, 4-chlorobenzyl-thiocarbamyl, 4-chlorobenzhydryl-thiocarbamyl, 4-butylmercaptobenzhydrylthiocarbarnyl, 3-[(4-amino-2-methyl-6-quinolinyl) -thio- 'carbamyl], Z-naphthyl-thiocarbamyl, 1-(4-chloronaphthyl)-thiocarbamyl, and the like.

When representing lower alkanesulfonyl, R is a saturated aliphatic sulionyl radical containing from one to 'six carbon atoms. Examples of such lower alkanesulfonyl radicals are methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, n-butanesulfonyl, isobutanesulfonyl, n-hexanesulfonyl, and the like.

When representing monocarbocyclic-arenesulfonyl, R is benzenesulfonyl or benzenesulfonyl substituted on the benzene ring by from one to three substituents of low molecular weight. Suitable substituents are lower alkyl, ilower-alkyl-oxy, nitro, halo, and lower-alkylmercapto groups. Examples of monocarbocyclic-arenesulfonyl groups are benzenesulfonyl, 4-toluenesulr'onyl, 4-chlorobenzenesulfonyl, 4-bromobenzenesulfonyl, 3-nitroben zenesulfonyl, 4-methoxybenzenesulfonyl, and the like.

When R represents monocarbocyciic aryl, monocarbocyclic-aryl-lower-alkyl having from one to three inert substituents on the aromatic ring, and bis(monocarbocyclic-aryl)methyl, the aryl portion is a member of the benzene series. Where substituents are present, they can be the same or difierent and can occupy any of the available positions on the aromatic ring, and they have total molecular weight less than 200. Suitable substituents are, for example, hydroxy, lower alkoxy, lower alkylmercapto, amino, di(lower alkyl)arnino, halo, loweralkyl, nitro, trifluorornethyl, and the like. monocarbocyclic aryl radicals encompassed by the invention include phenyl, 4-nitrophenyl, 3-chloro4-methylphenyl, Z-methoxyphenyl, 4-methylcercaptophenyl, 3- bromophenyl, 4-trifiuoromethylphenyl, 4-hydroxyphenyl, 4-dimethyl-aminophenyl, 4-iodophenyl, and the like. EX- amples of monocarbocyclic-aryl-lower-alkyl radicals encompassed by the invention include benzyl, 4-bromobenzyl, 4-nitrobenzyl, 4-trifluoromethylbenzyl, 3,4,5-trimethoxyphenylethyl, 4-aminophenylethyl, and the like. Examples of bis(monocarbocyclic-aryl)methyl radicals encompassed by the invention include benzhydryl, 4-butylmercaptobenzhydryl, 4-chlorobenzhydryl, 4,4'-diiodobcnz Examples of r d hydryl, 4-hydroxy-4-rnethoxybenzhydryl, 4,4-bis(dimethylarnino)benzhydryl, Z-chlorobenzhydryl, and the like.

When representing di(lower alkyl)sulfamyl, R is SO N(lower alkyl) where lower alkyl is defined above. Examples of diilower alkyl)sulfamyl include diethylsulfamyl, dimethylsujlfamyl, di(n-hexyl)sultamyl, and the like.

The compound 9-methyl-3,9-diazabicyclo[3.3.1]nonane is known in the art. Said compound is useful as a starting material for preparing many of the novel compositions of this invention by alkylation and acylation procedures, Suitable acylating agents are lower. alkyl esters of organic carboxylic and sulfonic acids, acyl halides, acyl anhydrides, isocyanates and isothiocyanates. Suitable alkylating agents are substitutedor unsubstituted-alkyl esters of strong acids, for example, substitutedor unsubstituted-alkyl halides, sulfates, and arylsulfonates. Alkylation can also be accomplished by other standard alkylation reactions, for example, reductive alkylation, Mannich. alkylation, cyanoethylation, and the like.

The compounds of Formula I substituted in the Z-position by a monocarbocyclic-aryl substituent, which are not available by the latter procedure, can be prepared by the following process: a diester of N-alkyl-piperidine-2,6- dicarboxyiic acid is heated at l50350 for 12-48 hours with aniline or a substituted aniline to produce 3-aryl-9- alkyl-2,4-dioxo-3,9-diazabicyclo[ 3 .3 i nonane, which is reduced with lithium aluminum hydride, or hydrogen over a suitable catalyst, to give 3-aryl-9-alkyl-3,9-diazabicyclo[3.3.l]nonane. The reduction is carried out in an inert reaction medium, preferably in an ether, for example, diethyl ether, tetrahydroturan, anisole, dibutyl other, and the like. It is desirable to carry out the reaction at the reflux temperature of the solvent employed, although in most cases reduction occurs slowly at room temperature.

The 3,9-diazabicyclo[3.3.l]nonanes are basic substances and are most conveniently used in the form of their water-soluble physiologically-acceptable acid-addition salts. Physiologically-acceptable salts are salts the anions of which are relatively innocuous to the animal organism when administered in the therapeutic dosages. Appropriate acid-addition salts are those prepared by the addition of mineral acids, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and from organic carboxylic and sulfonic acids, for example, acetic acid, citric acid, tartaric acid, lactic acid, giuconic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, meconic acid, p-chlorobenzenesulfon-ic acid, and the like.

Although the acid-addition salt forms preferably have anions which are pharmacologically acceptable, salts having toxic anions are also useful in that they may serve as characterizing derivatives of the free bases and serve as intermediates for non-toxic salts by way of ion-exchange reactions. All acid-addition salts, regardless of the nature of the anions, are useful as intermediates in the purification'of the free bases.

The acid-addition salt forms are prepared by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solvent, or by reacting the free base and the acid in an organic solvent, in which case the salt separates directly or can be isolated by concentrating the solution. The number of equivalents of acid which enter into salt formation depends upon the amount of acid present and upon the number of amino groups present in the free base. If an excess of acid is used, the number of equivalents of acid used will equal the number of basic nitrogens present in the free base.

T Still another aspect of my invention comprises the quaternary ammonium salt forms of the free bases shown in Formulas I and II. The quaternary ammonium salt forms are obtained by the addition of alkyl,

alkenyl, and aralkyl esters of inorganic acids or organic sulfonic acids to the free base form of the compounds. The alkyl, alkenyl, and arallcyl esters so used include such compounds as methyl sulfate, methyl benzenesulfonate, ethyl p-chlorobenzenesulfonate, benzyl chloride, benzyl bromide, p-nitrobenzyl chloride, o-chlorobenzyl, and the like.

The quaternary ammonium salts are prepared by mixing the free base and the allryl, allienyl, or aralkyl esters in an organic solvent. Heating may be used to facilitate the reaction, although salt formation in some cases takes place readily at room temperature. The quaternary ammonium salt separates directly or can be isolated by concentration of the solution. The number of equivalents of alkyl ester entering into salt formation depends upon the amount of ester present relative to the amount of free base and on the number of basic amino groups present in the free base. If an excess of alkyl halide or other ester is used as a quaternizing agent, some or all of the basic amino groups present in the free base may be quaternized, depending upon the reaction conditions such as the temperature.

Like the acidaddition salts, the quaternary ammonium salts are useful for characterizing the free bases of the invention. Hence, the toxicity or non-toxicity ot the particular anion associated with the quaternary cation is of little significance, and for this purpose a toxic quaternary ammonium salt can be as useful as a non-toxic one. It is possible to convert one salt to another having a different anion by conventional ion exchange reactions.

The compounds of my invention have been found by standard pharmacological and chemotherapeutic testing procedures to have spasmolytic, parasiticidal, and barbiturate potentiating activities, indicating their usefulness in the treatment of peptic ulcer and pylorospasm, in the treatment of schistosomiasis and amebiasis, and as adjuvants in producing barbiturate hypnosis.

The structures of the compounds were determined by their mode of preparation and by the correspondence of calculated and found values for elemental analyses of representative samples.

The following examples further illustrate the invention without the latter being limited thereto.

EXAMPLE 1A 3-1 enzy1-9-me2lzyl-2,4-diox0-3,9-ziiazabicyclo[3.3.1] nonane A mixture containing 208 g. (0.967 mole) of dimethyl scopolinate and 256 g. (2.56 moles) of benzylamine was heated at reflux for 48 hours. The excess benzylamine was distilled under reduced pressure, and the glassy residue remaining was extracted four times with one liter portions of hot n-hexane. The product was allowed to crystallize from the combined cooled extracts. The pure 3 -benzyl-9-methyl-2,4-dioxo-3,9-diazabicyclo 3 .3 1 nonane thus obtained melted at 114116 C. The monohydrochloride salt prepared from the free base melted with decomposition at 2020-2101) C. (corn).

EMMPLE 1B 3-benzy1-9-11:ethyZ-iQ-diambicyclo [3.3.1 nonane To a slurry of 4.8 g. of lithium aluminum hydride in 600 ml. of dry ether was added 14.2 g. of 3-benzyl-9- methy 2,4 dioxo-3,9-diazabicy clo[3.3.1]nonane. The mixture was stirred at room temperature for 72 hours. Absolute ethanol was then added dropwise, and the reaction mixture was made basic with an excess of sodium hydroxide solution. The mixture was then extracted with ether, and the solvent was distilled leaving a light oily residue of 3-benzyl-9-methyl-3,9-diazabicyclo[3.3.l]nonane. The monohydrogen citrate salt melted with decomposition at 1308-1375 C. (corr.).

6 EXAMPLE 1c 9-methyl-3,9-diazabicyclo[3.3.1]n0nane A solution containing 11.5 g. (0.05 mole) of 3-benzyl- 9 methyl 3,9 diazabicyclo[3.3.l]nonane in 150 ml. of ethanol was acidified with concentrated hydrochloric acid and was hydrogenated over 1.5 g. of 5% palladium-oncharcoal at 46 p.s.i. in a bottle-type hydrogenator. The theoretical quantity of hydrogen was absorbed in 7 hours. The suspended solids were collected and extracted several times with boiling water. The aqueous extracts were then combined with the filtrate and concentrated under reduced pressure leaving a solid consisting of 9methyl-3,9 diazabicycio[3.3.1lnonane dihydrochloride, which melted at 300 C. (corn).

EXAMPLE 2 3- (Z-dimeflzylaminoerhyl) -9-methy1-3,9-diazabicyclo [3.3.1lnane trihydrochloride EXAMPLE 3 E-cm'beflzmyQ-metlzyl-iQ-diaznbicyclo [3 .3 .1 1 nonane dihydrogen citrate A mixture containing 14.3 g. (0.07 mole) of 9-methyl- 3,9-diazabicyclo{3.3.11nonane, 25.2 g. (0.3 mole) or" sodium bicarbonate, 7.3 g. (0.07 mole) of ethyl chlorocarbonate, and 37 ml. of absolute ethanol was refluxed with stirring for 7 hours. The solvent was removed under reduced pressure, and the remaining solid was treated with hot water. The aqueous solution was made basic with 50% sodium hydroxide solution and the oil which separated was drawn off. The oil consisting of 3-carbethoxy-9-methyl-3 ,9'diazabicyclo [3 .3 l lnonane was distilled, Bl. 8l82 C. at 0.5 mm. The dihydrogen citrate salt melted with decomposition at 116.2- C. (corn).

XAMPLE 4 2,4-diox0-9-methyZ-3-phenyl-3,9-diazabicycl0 [3.3.1] nonrme Following the procedure given in Example 1A, 21.5 g. (0.1 mole) of dimethyl scopolinate was reacted with 23.3 g. (0.25 mole) of aniline. The excess aniline was re- 10V6l by steam distillation. The aqueous mixture was then repeatedly extracted with ether and the solvent was removed from the extracts. The remaining crude 2,4 dioxo 9 methyl 3 phenyl 3,9 diazabicycl0[3.3.1] nonane was crystallized from n-hexane giving pure 2,4-

'2" dioxo 9 methyl 3 phenyl 3,9 diazabicyclo[3.3.1] nonane which melted at 150.6155.0 C. (corn) EXAMPLE 5B 9-methyl-3-phenyl-3,9-diazabicyclo[3.3.1]nomme dihydrogen citrate Following the procedure given in Example 1B, 10.5 g. (0.043 mole) of 3-phenyl-9methyl-2,4-dioxo-3,9diazabicyclo[3.3.1]nonane was reduced with 3.55 g. of lithium aluminum hydride in dry ether. 9-methyl-3-phenyl-3,9- diazabicyclo[3.3.l]nonane was obtained as an amber oil. 9-methyl-3-phenyl-3 ,9-diazabi yclo [3 .3 .1 Jnonane dihydrogen citrate, prepared from the free base melted at 124.0- 128.4 C. (corr.).

EXAMPLE 6 3,9-dimethyl-3,9diazabicyclo[3.3.1]nomme dihydrochloride EXAMPLE 7 9-512ethyl-3-phenyIaz0-3,Q-diazabicyclo [3 3.1 nonane A chilled aqueous solution of 0.06 mole of benzenediazonium chloride was added to a solution containing 14.0 g. (0.066 mole) of 9-methyl-3,9-diazabicyclo[3.3.l] nonane dihydrochloride and 34 g. (0.25 mole) of sodium acetate trihydrate in about 50 ml. of water. The solution was stirred at 0 for an hour and allowed to warm to room temperature. The solution was thenrextracted with ether, and to the ether extracts was added ethereal HCl. The red oil which separated was crystallized with absolute ethanol. The crude 9-methyl-3-phenylazo-3,9- diazabicyclo[3.3.1]nonane hydrochloride was made basic with 35% sodium hydroxide solution and the resulting oil was distilled, giving pure 9-methyl-3phenylazo-3,9-diazabicyclo[3.3.1]nonane, boiling at 130 C. at 0.007 mm; n :1.6208.

EXAMPLE 8 3- (3-ind0lyl) methy l-9-methyl-3,9-diazabicyclo [3 .3.1 nomme An ice-cold solution containing 9.9 g. (0.07 mole) of 9-methyl-3,9-diazabicyclo[3.3.1]nonane, 9.8 g. of glacial acetic acid, 5.85 g. (0.068 mole) of 35% formalin, and 8.1 g. (0.069 moles) of indole was allowed to stand at roomtemperature for five days. The solution was then diluted with about 25 ml. of water and was made basic with 25 ml. of 50% sodium hydroxide solution. The basic solution was then extracted with benzene and the benzene solution was dried. The addition of n-pentane caused the crystallization of crude 3-(3-indolyl)methyl- 9-methyl 3,9 diazabicyclo[3.3.1]nonane. Recrystallized from n-hexane, the pure 3-(3-indolyl)methyl-9-methyl- 3,9-diazabicyclo[3.3.1]nonane melted at 144-149.4 C. (corn).

EXAMPLE 9A 3-benzyl-7-meth0xy-9-methyl-2,4-diox0-3,Q-aiczzabicyclo[3.3.1] nonane Following the procedure given in Example 1A, 1.29 moles of benzylamine was reacted with 0.514 mole of dimethyl 4-methoxy-1-methyl-2,6-piperidinedicarboxylate (prepared by catalytic reduction of dimethyl 4-methoxy- 2,6-pyridinedicarboxylate, followed by reductive methylation of the resulting dimethyl 4-meth0Xy-2,6-piperidincdicarboxylate). Recrystallized from n-pentane the prodnet, 3 benzyl-7-methoxy-9-methyl-2,4-dioxo3,9-diazabicyclo[3.3.1]nonane melted at 6668 C. The mono-hydrochloride salt melted with decomposition at 167.8- 174.2 C. (corn).

. EXAMPLE 9B E-benzy l-7-meth0xy-9-methyl-3,9-diazabicycl0 [3 .3 .1 nonane Following the procedure given in Example 13, 3-benzyl 7 methoxy 9 methyl 2,4 dioxo 3,9 diazabicyclo[3.3.1]nonane was reduced with lithium aluminum hydride in absolute ether to give 3-benzyl-7-methoxy-9- methyl-l9- iazabicyclo[3.3.1]nonane, boiling at 127 C. at 0.02 mm. A crude sample of the citrate salt melted with decomposition at C.

The following compounds are prepared according to the procedure given in Example 1A, using the designated amine in place of b-enzylamine:

3 (3 chloro 4 methylphenyl) 9 methyl 2,4 dioxo3,9-cliazabicyclo[3.3.1]nonane, melting at 138.4- 148.6 C. (corn), from 4-met'nyl-3-chloroaniline;

3 (4 nitrophenyl) 9 methyl 2,4 dioxo 3,9 diazabicyclo 3 .3 1 1 nonane from 4-nitroaniline;

3 (3 methoxyphenyl) 9 'nethyl 2,4 dioxo 3,9- diazabicyclo[3.3.1]nonane from 3-anisidine;

3 (4 methylmercaptophenyl) 9 methyl 2,4 dioxodiazabicyclo [3 .3. l nonane from 4-thioanisidine;

3 (3 bromophenyi) 9 methyl 2,4 dioxo 3,9- diazabicyclo[3.3.1]nonane from 3-bromoaniline;

3 (4 trifluoromethylphenyl) 9 methyl 2,4 dioxo- 3 ,9-diazabicyclo [3.3.1 Jnonane from 4-trifiuorornetl1ylaniline;

3 (4 hydroxyphenyl) 9 methyl 2,4 dioxo 3,9- diazabicyclo[3.3.1]nonane from 4-hydroxyaniline; and

3 (4 dimethylaminophenyl) 9 methyl 2,4 dioxo- 3 ,9-diazabicyclo [3 .3 l 1 nonane from 4-dimethylaminoaniline.

The following compounds are prepared according to the procedure given in Example 15 by reduction of the corresponding 2,4-dioxo 3,9 diaza'oicyclo[3.3.1]nonane mentioned above:

3 (3 chloro 4 methylphenyl) 9 methyl 3,9 diazabicyclo[3.3.1]nonane dihydrogen citrate, melting at 127.6-1304" C. (corn);

3 (4 aminophenyl) 9 methyl 3,9 diazabicyclo [3.3.1]nonane, from the corresponding 4-nitrophenyl compound, above;

3 (3 methoxyphenyl) 9 methyl 3,9 diazabicyclo [3.3.1]nonane;

3 (4 methylmercaptophenyl) 9 methyl 3,9 diazabicyclo 3 .3 1 nonane;

3 (3 bromophenyl) 9 methyl 3,9 diazabicyclo [3.3.1]nonane;

3 (4 trifluoromethylphenyl) 9 methyl 3,9 diazabicyclo [3.3.1 ]nonane;

3 (4 hydroxyphenyl) 9 methyl 3,9 diazabicyclo [3.3.1]nonane; and

3 (4 dimethylaminophenyl) 9 methyl 3,9 diazabicyclo[3.3.l]nonane.

Following the procedure given in Example 3, the following compounds are prepared by reacting 9-methyl-3,9 diazabicyclo[3.3.1]nonane with the designated acylating agent:

3 diethylcarbamyl --9 methyl 3,9 diazabicyclo [3.3.1]nonane dihydrogen' citrate, melting with a decomposition at l41.2-144.6 C. (corn), from diethylcarbamyl chloride;

3-ethanesulfonyl 9 methyl 3,9 diazabicyclo[3.3.1] nonane, melting at 63.2-66.0 C. (corn), from ethanesulfonyl chloride;

3 dimethylsulfamyl 9 methyl 3,9 diazabicyclo [3.3.1]nonane hydrochloride, melting with decomposition 9 at 247.4-249.0 C. (corn), from dimethylsulfamyl chloride;

9 methyl 3 (4-methylphenylsulfonyl)-3,9- iazabicycio[3.3.l]nonane dihydrogen citrate, melting with decomposition at 72.4-92.4" C. (corn), from 4-toluenesulfonyl chloride; and

3 (4 methoxyphenylsulfonyl) 9-methyl-3,9-diazabicyclo[3.3.l]nonane, melting at 137.S143.8 C. (corn), from 4-methoxyphenylsnlfonyl chloride.

Following the procedure given in Example 4, the followlowing compounds are prepared from 9-methyl-3,9-diazabicyclo[3.3.l]nonane and the designated isocyanate or isothiocyanate:

3 [(4 butylinercaptobenzhydryl)thiocarbamyl] 9 methyl-3,9-diazabiocyclo [3.3.1]nonane dihydrogen citrate, melting with decomposition at 1242-1452 C. (corn), from 4-butylmercaptobenzhydrylisothiocyanate;

3 [(4 clilorohenzhydryl)carhamyl] 9 methyl-3,9- diazabicyclo[3.3.1]nonane dihydrogen citrate, melting with decomposition at 169.4-17L4" C. (corn), from 4- chlorooenzhydrylisocyanate;

3 carbamyl 9 methyl-3,9-diazahicyclo[3.3.11nonane, melting at 175.4-i78.6 C. (corn), from potassium cyanote;

3 (ailylthiocarhamyl) 9 methyl 3,9 diazabicyclo[3.3.1}nonane dihydrogen citrate, melting at 75.6- 84.6" C. (corn), from allylisothiocyanate;

3-(4-chiorobenzylthiocarbamyl) 9 methyl 3,9-diambicyclo[3.3.l}nonane, melting at l44.6l46.3 C. (corn), from 4-chlorobenzylisothiocyanate;

3 [(4 amino 2 methyi-fi-quinolinyl)thiocarbamyl} 9-rnethyl-3,9-diazahicyclo[3.3.ljnonane phosphate, melting with decomposition at 229.6231.2 C. (cont), from 4 amino Z-methyl-6-qninolinyiisothiocyanate, which is prepared according to known procedures from 4,6-diaminoquinaldine and thiophosgene;

3 thiocarbamyl 9 methyl-3,9-diazabicyclo[3.3.1]nonane, from potassium thiocyanate; and

3 (2 naphthylthiocarbamyl) 9 methyl-3,9-diazabicyclo [3.3.1]nonane, from Z-naphtnylisothiocyanate.

Following the procedure given in Example 2, the following compounds are prepared from 9methyl-3,9-diazabicyclo[3.3.l]nonane and the designated alkylating agent:

3 (2 methylmercaptoethyl) 9 methyl-3,9-diazabicyclo[3.3.l]nonane dihydrogen citrate, melting with decomposition at 136.8-l37.8 C. (corn), from 8-methylmercaptoethyl bromide;

3 (2 hydroxyethyl)-9-methyl-3,9-diazabcyclo[3.3.1]- nonane clihydrogen citrate, melting at 112.2-1 144 C (corr.), from ethylenebromohydrin;

3 dimethylaminopropyl 9 methyl 3,9 diazabicy clo[3.3.l]nonane trihydrochloride, melting at 227.6- 2338 C. (corn), from 3-dimethyiaminopropyl bromide. The methobromide, which was extremely hygroscopic, melted at 279.6-2814" C. (corn);

3 (4 chlorohenzhydryl) 9 methyl-3,9-diazabicyclo- [3.3.1]nonane dihydrogen citrate, which melted indefinitely starting at 193.6" C. (corn), from 4-chlorobenzhydryl chloride;

3 [3 (4 carbethoxy-l-piperazinyl)propyl1-9-methyl- 3,9diazabicyclo[3.3.1]nonane phosphate, melting with decomposition at 1894-1821? C. (corn), from 3-(4-Carbethoxy-l-piperazinyl)propyl chloride; the free base was an oil having a refractive index, 11 215074;

3 (3 hydroxypropyl) 9 methyl-3,9-diazabicyclo- [3.3.1]nonane dihydrogen citrate, melting with decomposition at 75 .2-96.0 C. (corn), from trimethylene brornohydrin;

The 3,4,5-trimethoxybenzoic acid ester of 3-(3-hyclroxypropyl)-9-methyl-3,9-diazahicyclo[3.3.13nonane dihydro gen citrate, melting with decomposition at 97.2-99.4 C. (corn), was prepared by reacting the latter compound with 3,4,5-trimethoxybenzoyl chloride;

3 (3,4,5 trimethoxyphenylethyl) 9 methyl-3,9-diazabicyclo[3.3.l]nonane dihydrogen citrate, melting with 1% decomposition at 144-.6-1462" C. (corn) from 2-(3,4,5- trimethoxyphenyl)ethyl bromide;

3 carbethoxymethyl-9-methyl-3,9-diazabicyclo[3.3.l]- nonane dihydrogen citrate, melting at 1G2.4-l06.4 C. (corn), from ethyl chloroa-cetate;

3 (carbo-Z-diethylaminoethoxy)methyi-9-rnethyl-3,9- diazabicyclo[3.3.11nonane, boiling at 113 C. at 0.02 1nm., 1z :1.4-849, was prepared from 3-carbethoxymethyl-9-methyl-3,9-diazabicyclo[3.3.1]nonane by cross-esterification of the latter with Z-dimethylaminoethanol;

3 (l hydroxy 1,2,3,4 tetrahydro-Z-naphthyl)-9 methyl-3,9-diazahicyclo [3.3.1]nonane dihydrogen citrate, melting with decomposition at 1422-1452 C. (corn), from 2-bromo-1-tetralol;

3 (4 butylrnercaptobenzhydryl) 9 methyl3,9-diazabicyclo[3.3.l]nonane dihydrogen citrate, melting with decomposition at 76.8-l01.2 C. (corn), from 4-butylmercaptohenzhydryl chloride;

3 [2 (4 methyl 1 piperazinyl)ethyl1-9-methyl- 3,9-diazabicyclo[3.3.1]nonane dimecorate, ielting with decomposition at i84 C. (corn), from 2(4-methyl-1-piperazinyl)ethyl chloride;

3 [2 (9 carbazolyDethyl] 9 methyl-3,9-diazabicyclo[3.3.l]nonane dihydrochloride, melting at 238.8- 239.4 C. (corn), from 2-(9-carbazolyl)ethyl chloride;

9 methyl 3 propargyl 3,9 diazabicyclo[3.3.l]nonane dihydrogen citrate, melting at 1290-1321) C. (corn from propargyl bromide;

9-methyl-3 -allyl-3 ,9-diazabicyclo [3 .3 1 lnonane dihydrogen citrate, melting at l23.4-l24.4 C. (corn), from allyl bromide;

3 diethylcarbamylmethyl 9 methyl-3,9-diazabicyclo [3.3.1]nonane phosphate, melting indefinitely starting at 152.4 C. (corn), from N,N-diethyl chloroacetamide;

9 methyl 3 (4-nitrobenzyl)-3,9-diazabicyclo[3.3.1] nonane monohydrogcn citrate, melting with decomposition at 177.0-177.9 C. (corn), from 4-nitrobenzyl chloride;

3 (2 chlorohenzhydryl) 9-methyl-3,9-diazabicyclo [3.3.1]nonane dihydrogen citrate, melting with decomposition at MRS-114.6 C. (corn), from Z-chlorobenzhydryl chloride;

3 (2,4-dichlorobenzyl) 9 methyl 3,9 diazabicyclo [3.3.1]nonane (lihydrochloricle, melting indefinitely starting at 190.4 C. (corn), from 2,4-dichlorobenzyl chloride;

3 (5 mcthylaminopentyl) 9-methyl-3,9-diazabicyclo [3.3.1]nonane from 1chlore-5-methylaminopentane;

3 (6 aminohexyl) 9-methyl-3,9-diazabicyclo[3.3.1] nonane from l-chloro-o-aminohexane; and

3 (2 ethoxyethyl) 9-methyl-3,9-diazabicyclo[3.3.1] nonane from ethoxyethyl chloride.

I claim:

1. A compound of the formula CHFCH-CHZ CH2 N-CHz N-R 011 -0 '-oH wherein R is lower alkcnyl.

2. A compound of the formula 3. A compound of the formula CHFOHCH3 CH2 NCH3 NR GIn-OH CHQ wherein R is hydroxyiower-alkyl.

1 1 4. A compound of the formula OH2CHCH2 0H2 N-CH3 NB o112oH-oz wherein R is a member of the group consisting of benz hydryl and benzhydryl in which at least one benzene ring thereof is substituted with from one to three substituents selected from the group consisting of hydroxy, lower alkoxy, lower alkylrnercapto, amino, di(lower alkyl)amin0, halo, lower alkyl, nitro and trifluoromethyl.

5. 3 (3 chloro 4-rnethylphenyl)-9-metl1yl-3,9-diazabicyclo [3 .3 1 nonane.

6. 3-allyl-9-methyl-3 ,9-diazahicyclo [3 .3 .1 nonone. 7. 3 carbethoxy 9 methyl-3,9-diazabicyclo[3.3.1]

nonane.

8. 3 diethylcarbamyl-9-methyl-3,9-diazabicyclo[3.3.1]

nonane.

9. 3 [(4 chlorobenzhydryl)thiocarbarnyl]-9-methyl- 3 ,9-diazahicyclo [3 .3 .1]nonane.

1t). 3-[ (4-amino-2-rnethyl-6-quinolinyl)thiocarb amyl] 9-methyl-3 ,9-diazabicyclo [3 .3 .1 nonane.

1.1. 3 (4 methylphenylsulfonyl)-9-methyl-3,9-diazabicyclo [3.3 .1 kronane.

12. 3- (3 hydroxypropyl) 9-rnethyl-3,9-diazabicycl-o [3.3.1]nonane.

13. 3 (2,4-dichlorobenzyl)-9-methyl-3,9-diazabicyclo [3.3;1]nonane.

14. 3 (4 butylmercaptobenzhydryl) 9-methyl-3,9- diazabicyclo [3 .3 .1 1 nonane.

15; 9 methyl 3 phenylazo-3,9-diazabicyclo[3.3.1]

nonane.

16. 3 (3 indolyDmethyl 9-rnethyl-3,9-diazabicyclo [3.3.1]nonane. v '7. 3 (3-chloro-4-methylphenyl)-9-methyl-2,4-dioxo- 3 ,9-diazabicyclo [3.3 1 lnonane.

18. 3 benzyl 7 methoxy-2,4-dioxo-9-methyl-3,9-diazabicyclo 3 .3 1 nonane. 19. 3 benzyl 7 methoXy-9-rnethyl-3,Q-diazabicyclo [3.3.1]nonane.

2t). 3 R 9 methyl 3,9-diazabicyclo[3.3.1]nonane, wherein R is a member selected from the group consistrng of: (a) lower alkyl substituted by from one to three substituents selected from the group consisting of hy- 12 droxy, lower alkyl-O, lower alkylmercapto, di- (lower alkyDcarbarnyl, lower alkyl-OCO-, and carbo-w-di (lower alkyl) aminoalkyl-oxy;

(b) lower alkenyl;

(0) lower alkynyl;

(d) carbamyl;

(e) thiocarbamyl land thiocarbamyl substituted by a member of the group consisting of allyl phenyl, naphthyl; pyridyl, furyl; quino linyl; benzyl; benzhydryl; and phenyl, naphthyl, pyridyl, furyl, quinolinyl, benzyl and oenzhydryl in which at least one ring thereof is substituted with from one to three substituents selected from the group consisting of hydroxy, lower alkoxy, lower alkylmercapto, halo, nitro, lower alkyl, amino and trifiuoromethyl;

(f) lower alkanesulfonyl;

g) benzenesulfonyl and benzenesulfonyl substituted with from one to three substituents selected from the group consisting of lower alkyl, lower alkyloxy, nitro, halo and lower alkyl-mercapto;

(h) di(lower alkyl)sulfamyl; and

(i) benzhydryl and benzhydryl in winch at least one benzene ring thereof is substituted with from one to three substituents selected from the group consisting of hydroxy, lower alkoxy, lower alkyl-rnercapto, amino, di lower alkyDamino, halo, lower alkyl, nitro and trifluoromethyl.

References Cited by the Examiner Barnes et al.: Journal American Chemical Society, volume 75, pages 979-977 (1953).

Blackman et 211.: Journal Organic Chemistry, volume 26, pages 2756-2755 (1961).

Cignarella et 211.: Gazzetta Chima. Ital, volume 90, pages 14951504 (1960).

Rubtsov et al.: Journal Medicinal and Pharmaceutical Chemistry, volume 3, No. 3, pages 441-459 (May 18, 1961).

Schipper et al.: lournal Organic Chemistry, volume 26, page 35993602 (1961).

NICHOLAS S. RIZZO, Primary Examiner.

IRVING MARCUS, WALTER A. MODANCE,

Examiners. 

20. 3-R-9-METHYL-3,9-DIAZABICYCO(3.3.1)NONANE, WHEREIN R IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF: (A) LOWER ALKYL SUBSTITUTED BY FROM ONE TO THREE SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF HYDROXY, LOWER ALKYL-O-, LOWER ALKYLMERCAPTO, DI(LOWER ALKYL)CARBAMYL, LOWER ALKYL-O-CO-, AND CARBO-W-DI(LOWER ALKYL)AMINOALKYL-OXY; (B) LOWER ALKENYL; (C) LOWER ALKENYL; (D) CARBAMYL; (E) THIOCARBAMYL AND THIOCARBAMYL SUBSTITUTED BY A MEMBER OF THE GROUP CONSISTING OF ALLYL PHENYL, NAPHTHYL; PYRIDYL, FURYL; QUINOLINYL; BENZYL; BEZHYDRYL; AND PHENYL, NAPHTHYL, PYRIDYL, FURYL, QUINOLINYL, BENZYL AND BENZHYDYL IN WHICH AT LEAST ONE RING THEREOF IS SUBSTITUTED WITH FROM ONE TO THREE SUBSTITUENTS SELECTED FROM THE GROUP CONSITING OF HYDROXY, LOWER ALKOXY, LOWER ALKYLMERCAPTO, HALO, NITRO, LOWER ALKYL, AMINO AND TRIFLUOROMETHYL; (F) LOWER ALKYANESULFONYL; (G) BENZENESULFONYL AND BENZENESULFONYL SUBSTITUTED WITH FROM ONE TO THREE SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL, LOWER ALKYLOXY, NITRO, HALO AND LOWER ALKYL-MERCAPTO; (H) DI(LOWER ALKYL)SULFAMYL; AND (I) BENZHYDRYL AND BENZHYDRYL IN WHICH AT LEAST ONE BENZENE RING THEREOF IS SUBSTITUTED WITH FROM ONE TO THREE SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF HYDROXY, LOWER ALKOXY, LOWER ALKL-MERCAPTO, AMINO, DI(LOWER ALKYL)AMINO, HALO, LOWER ALKYL, NITRO AND TRIFLUOROMETHYL. 